We propose a study of genetic interactions in familial hypercholesterolemia (FH) using epidemiologic and molecular genetic techniques. Observations among FH pedigrees with multiple lipoprotein phenotypes suggest high coronary heart disease (CHD) risk among persons with FH and apolipoprotein E2 due to accumulation of excess beta-VLDL. Other studies suggest an interaction between FH and lipoprotein(a) [Lp(a)] which may increase CHD risk, though the interaction remains controversial. These interactions may help explain the clinical diversity seen in FH (age of CHD onset in FH females varied from 29 to 74 in one large pedigree). Moreover, FH provides a natural experimental model where an alteration in LDL receptor activity may enhance and clarify the metabolic consequences of molecular variants at other loci and provide further insights into their potential role in atherogenesis. We plan to examine detailed lipid profiles in 1200 persons from approximately 10-12 FH pedigrees for whom the LDL receptor defect will be defined by a collaboration with Helen H. Hobbs in Dallas. This will enable us to examine whether different LDL receptor defects interact differently with other genetic loci such as apo E and Lp(a). In 400 FH adults (age greater than 20) we will also perform high resolution B-mode ultrasonography of carotid and femoral arteries to determine whether FH patients with increased beta-VLDL levels (associated with apo E2) or increased Lp(a) have greater intima+media thickness in these vessels. Effects of standard cardiovascular risk factors such as blood pressure, HDL, smoking, and diabetes will also be considered in multivariate analysis. Coronary endpoints will be examined in a similar fashion. We will determine whether pedigree and individual heterogeneity with regard to these risk factors and interactions contributes to the diversity of clinical atherosclerosis expression in FH. We have also arranged a collaboration with Angelo Scanu, at University of Chicago, and Helen Hobbs in Dallas, to compare genotyping of the Lp(a) locus using pulsed field gel electrophoresis of DNA with a recently improved method (by Dr. Scanu) for determining apo(a)size isoforms using immunoblotting. These data will provide an important opportunity to sort out the conflicting evidence for an Lp(a) interaction with FH.